Behavioral interventions for obesity include prescribed energy reduction (ER) to promote weight loss, and these ER levels typically remain unchanged during the weight loss phase of treatment. While more stringent ER (e.g., >1,000 kcal/d deficit) produces greater and more rapid weight loss, such deficits are more difficult to follow and sustain over time than are moderate ER (e.g., ~500 kcal/d deficit). However, research is lacking on the efficacy of different ERs that alternate individuals between discrete episodes of stringent and moderate ER during obesity treatment. While varying ER during obesity treatment has not been rigorously evaluated, doing so may have psychological and behavioral advantages (increased novelty, engagement) as well as metabolic benefits (attenuated changes in resting metabolic rate and appetite-regulating hormones). Preliminary evidence also suggests: 1) variable ER produced significant short-term weight loss that was greater than losses achieved with a fixed ER, 2) adherence to the variable ER was good, and 3) participants expressed positive attitudes about this alternative approach. Collectively, these findings indicate that variable ER may offer an efficacious strategy for improving weight loss and weight loss maintenance. As such, we propose to conduct a lifestyle intervention weight loss trial to compare the short- and long-term effects of two ER prescriptions: 1) a conventional, fixed energy reduction (FER) that includes a 750 kcal/d deficit, and 2) a variable energy reduction (VER) that includes alternating at 2-week intervals between 500 and 1,000 kcal/d deficits. This 18-month trial will include 218 obese adults completing an intensive lifestyle intervention consisting of an initial 6 months of weekly treatment contacts, 6 months of bi-weekly contacts, and 6 months of observational follow-up. The primary outcome will be changes in body weight at month 18. Secondary outcomes will include changes in energy expenditure, body composition, fasting glucose, lipids, blood pressure, and weight-regulating hormones. Dietary adherence, hunger/satiety, and treatment satisfaction will also be assessed. This is a novel investigation, as no previous trial has rigorously examined VER as an alternative to a conventional FER. If VER produces superior outcomes, it would have significant clinical implications for the delivery of obesity treatment and dietary recommendations provided to participants. By examining a variety of behavioral, psychological, and biological variables, this study may provide additional information about potential mechanism by which different ER prescriptions promote weight loss and weight loss maintenance.